Malignant melanoma as a target malignancy for the study of the anti-metastatic properties of the heparins

Abstract

The outlook for metastatic melanoma to the brain is dismal. New therapeutic avenues are therefore needed. The anti-metastatic mechanisms that may underpin the effects of low molecular weight heparins (LMWHs) in in vitro and preclinical melanoma models warrant translating to a clinical setting. This review outlines a rationale that supports our proposal that metastatic melanoma to the brain is a clinical setting in which to study the anti-metastatic potential of LMWHs. Prevention or delay of brain metastases in melanoma is a clinically relevant and measurable target. Studies to explore the effect of anticoagulants on cancer survival are underway in other malignancies such as lung, pancreas, ovary, breast, and stomach cancer. However, no study to our knowledge has a methodology that could produce clinical evidence in support of a mechanism for whatever benefit may be seen. The setting we propose would allow translation of the molecular knowledge of the metastatic pathways mediated by platelets and the selectins--all potential targets of heparin--in a "time to appearance" of brain metastases endpoint. Since brain metastases are so common and they have a singularly adverse impact on survival, the "biological neuroprotection" model we propose in metastatic melanoma could provide the translational evidence to support the benefit of LMWHs in melanoma. More significantly, this would open the door to a wider "anti-metastatic" approach that could have much greater impact in patients with minimal disease being treated in adjuvant settings for the more common malignancies such as breast and colon cancer.

Fig. 1

Potential role of heparin–selectin interaction in melanoma metastasis. a Platelet–tumor cell microemboli formations are primarily mediated by P-selectin and platelet aggregation. L-selectin mediates the recruitment of leukocytes to tumor cells. These “transit” metastatic emboli include leucocytes and function as vehicles that shield the tumor cell from shear force and immunosurveillance (NK cells). The expression of E- and P-selectin on endothelial cells initiates tethering and rolling of tumor cells. This weak adhesion to the endothelium promotes establishment of the “metastatic niche” usually associated with more “definitive” binding to intercellular cell adhesion molecules. b Heparins bind to selectins and inhibit their function